, Description:FIELD OF THE INVENTION
The present invention relates to a process for preparation of crystalline Ambroxol Hydrochloride (I)
(I)
BACKGROUND OF THE INVENTION
Ambroxol Hydrochloride is chemically described as Trans-4-[(2-amino-3,5-dibromophenyl) methylamino] cyclohexan-1-ol hydrochloride is represented by formula (I) is a secretolytic agent (expectorant).
(I)
Ambroxol Hydrochloride was developed by Boehringer-Ingelheim in the late 1960s and 1970s and commercialized in 1978. Ambroxol Hydrochloride is used to treat bronchopulmonary diseases by clearing mucus from the lungs. It is marketed under several trade names, such as Mucosolvan® and Lasolvan® often as the active ingredient in cough syrups.
In India, it is approved by CDSCO on Dec 01, 1995 and on May 25, 2018 EMA has approved Ambroxol for the treatment of amyotrophic lateral sclerosis. Ambroxol is not approved by USFDA.
Earlier, several processes are reported for the preparation of Ambroxol Hydrochloride, which are summarized herein below.
Johannes Keck et al. in US 3536713A discloses the preparation of Ambroxol by bromination of N-(trans-p-hydroxy-cyclohexyl)-(2-aminobenzyl)-amine. The process involves the use of chromatographic column, which is not feasible for industrial scale production. Hence, due to the lengthy isolation procedure the product formed was very less in quantity and hence not commercially feasible.

Scheme-1: Process as per US 3536713A

Dr. Liebenow Walter et al. in EP0130224B1 discloses the preparation of Ambroxol from methyl anthranilate in five steps via bromination, hydrazinolysis, mesylation, condensation with cyclohexanolamine, and Schiff’s base reduction steps. The process involves the bromination of methyl anthranilate with bromine results in the formation of Methyl 2-amino-3,5-dibromobenzoate. Methyl 2-amino-3,5-dibromobenzoate upon hydrazinolysis with hydrazine hydrate gives 2-amino-3,5-dibromobenzohydrazide. Mesylation of 2-amino-3,5-dibromobenzohydrazide gives N'-(2-amino-3,5-dibromobenzoyl) methanesulfonohydrazide which on condensation with trans-cyclohexanolamine gives (1r,4r)-4-((E)-(2-amino-3,5-dibromobenzylidene)amino)cyclohexanol further upon reduction in presence of sodium borohydride and methanol results in the formation of Ambroxol.
Due to the involvement of the large number of steps, it makes the process difficult and tedious to be performed on large scale, besides several steps impurities formation and their carryover concerns.

Scheme-2: Process as per EP0130224B1
Ravajibhai Kalpesh Patel et al. in IN 312968 discloses the preparation of Ambroxol from bromination of methyl anthranilate to give 3,5-dibromo methyl anthranilate which on reduction gives 3,5-dibromo2-aminobenzyl alcohol which upon oxidation give 2-amino-3,5-dibromobenzaldehyde and on condensation with Trans-4-aminocyclohexanol produces Trans-4-(2-amino-3,5-dibromobenzyldeneamino) cyclo hexanol which reduces to give Ambroxol free base and on treatment with Hydrochloric acid in isopropyl alcohol gives Ambroxol hydrochloride.
Process involves several numbers of steps with critical reagents which is not suitable for bulk production. The isolation of Manganese dioxide used in the conversion of compound of (III) to compound of formula (IV) is also a very tough task.

Scheme-3: Process as per IN 312968
M. R. Caira et al. in Journal of Thermal Analysis and Calorimetry (2004), 77(2), 653-662 discloses the polymorphic Form I (m.p. 99.5°C), Form II (m.p. 92.4°C) and Form III of Ambroxol free base, however –none of the crystalline form was found related with its hydrochloride salt. The crystalline forms of AMB (free base) were obtained by dissolving AMB hydrochloride in water (13 g L–1 at 60°C) and by adding dropwise, under stirring, aqueous NaOH (4% by mass) up to a pH value of ~9.5. The resulting suspension was then allowed to stand overnight at 4°C and suction filtered. The recovered solid was thoroughly washed with cold water and air dried at ambient temperature. Single polymorphs of AMB is isolated from water–ethanol 1:1 mixture, based on the recrystallization procedure. When the hot solution is allowed to cool spontaneously to ambient temperature, a microcrystalline precipitate (AMB I) is obtained. On standing for several days, long thin needles of AMB II separate from the filtrate. Slow cooling of a single crystal of Form I on the diffractometer from 24°C to –70°C over a period of 2 h led to a single crystal to single crystal transformation to Form III (Ambroxol free base).
The characteristic diffraction peaks of Form (I) can be observed at 7.1 and 20.6° (2?) and of Form (II) at 7.4, 8.3, 14.8, 22.7 and 30.0° (2?).
Huang Mutong et al. in CN102964257B disclosed a crystalline form of Ambroxol Hydrochloride having XRPD peaks at a diffraction angle at 6.9°, 7.2°, 10.2°, 12.5°, 15.8°, 20.2°, 29°, 32°, 35.2° by converting Ambroxol free base into its hydrochloride salt, however, exact process appears to be unclear.
Inventors of the present invention prepared a novel stable crystalline form designated as “Form SAH” of Ambroxol Hydrochloride, which is not only easy to handle and environment friendly, but also amenable to commercial scale with consistency and reproducibility. The novel Crystalline Form-SAH of Ambroxol Hydrochloride is found to be stable and pharmaceutically acceptable to make their therapeutic dosage forms. This stable form offers various advantages in terms of storage, shelf life and favorable impurity profile.
SUMMARY OF THE INVENTION
Particular aspects of the present invention relates to the process for preparing crystalline Ambroxol Hydrochloride (I),
(I)
comprising the steps of:
a) treating Ambroxol free base with ketone (C3-C6) solvent in a ratio ranging between 1 (Ambroxol base) : 4 -7 (ketone solvent) (w/v);
b) adding concentrated hydrochloric acid till achieving pH range between 1.2 to 1.6 in time duration ranging between 2-5 hours at temperature ranging between 15-25°C
c) stir the reaction mass of step b) for time duration ranging between 2-5 hours at temperature ranging between 15-25°C
d) filter the crystalline Ambroxol Hydrochloride
e) Optionally purify the crystalline Ambroxol Hydrochloride with a ketone (C3-C6) solvent to get crystalline Ambroxol Hydrochloride.
In yet another aspect the present invention also relates to highly pure crystalline Crystalline Ambroxol hydrochloride material (designated as Form-SAH) having purity exceeding 99.8% (by HPLC).
The novel stable crystalline Form-SAH of Ambroxol Hydrochloride is characterized by X-ray powder diffraction pattern comprising of 2?° diffraction angle peaks at 7.1, 13.0, 15.8, 17.5, 20.6, 21.2, 22.6, 23.5, 24.0, 25.1, 27.6, 28.4, 32.2, 35.7 ± 0.2 2?°.
The Crystalline Form-SAH is further characterized by FT-IR spectral absorption peaks selected from 1778 cm-1, 1632 cm-1, 1300 cm-1, 1285 cm-1,658 cm-1 , 634 cm-1, 578 cm-1 and 541 cm-1; and DSC isotherm endothermic peak ranging between 243-246°C.
In yet another aspect of the present invention, it relates to the Highly pure crystalline Ambroxol Hydrochloride (Form-SAH), wherein the Crystalline Form-SAH is characterized by cis-4-[(2-amino-3,5-dibromobenzyl]amino] cyclohexanol and trans-[4-(6,8-dibromo-1,4-dihydroquinazoline-3 (H)] cyclohexanol hydrochloride content less than 0.02% and (2-amino-3,5-dibromophenyl) formaldehyde content is absent.
Further particular aspects of the invention are detailed in the description part of the specification, wherever appropriately desired.
BRIEF DESCRIPTION OF THE DRAWINGS:
FIG. 1 is an illustration of X-ray powder diffraction pattern of compound of formula (I)
FIG. 2 is an illustration of FTIR absorption spectrum of compound of formula (I)
FIG. 3 is an illustration of DSC thermogram pattern of compound of formula (I)

DETAILED DESCRIPTION:
Embodiments according to present invention provides a commercially amenable process for preparing highly pure crystalline Ambroxol Hydrochloride, which is stable and suitable for preparing therapeutic dosage forms.
In one embodiment of the present invention, it provides a process for preparing highly pure crystalline Ambroxol Hydrochloride (I)
(I)
comprising the steps of:
a) treating Ambroxol free base with ketone (C3-C6) solvent in a ratio ranging between 1 (Ambroxol base) : 4 -7 (ketone solvent) (w/v);
b) adding concentrated hydrochloric acid till achieving pH range between 1.2 to 1.6 in time duration ranging between 2-5 hours at temperature ranging between 15-25°C
c) stir the reaction mass of step b) for time duration ranging between 2-5 hours at temperature ranging between 15-25°C
d) filter the crystalline Ambroxol Hydrochloride
e) Optionally purify the crystalline Ambroxol Hydrochloride with a ketone (C3-C6) solvent to get crystalline Ambroxol Hydrochloride.
Individual steps of the embodiments are detailed herein below.
In step a), the treating of Ambroxol free base with ketone (C3-C6) solvent in a ratio ranging between 1 (Ambroxol base): 4 -7 (ketone solvent) (w/v) is performed at room temperature, however, critical parameter is to use ketone solvent in a ratio of ranging between 4 to 7 times w.r.t. Ambroxol free base. In a more preferred embodiment, it is used as 5-6 times w.r.t. Ambroxol free base.
In a particular embodiment, it was used 5.5 times w.r.t. Ambroxol free base.
The ketone (C3-C6) solvent used in the present invention are selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone or in combination thereof.
In particular embodiment according to present invention,the ketone solvent used in step a) and step e) was acetone or methyl ethyl ketone or in combination thereof.
The step b) of hydrochloride salt formation of Ambroxol free base was performed by adding concentrated Hydrochloric acid in time duration of ranging between 2-5 hours. More particularly 2-3 hours at a temperature range of 18-22°C was observed more appropriate. The pH range of the reaction mass after adding conc hydrochloric acid was observed critical and found by inventors of the present invention to be maintained between range of 1.2-1.6.
Inventors of the present invention have observed that the pH range is critical for the formation of Ambroxol Hydrochloride from its free base. The observed pH range is found to be satisfactory for complete hydrochloride salt formation of Ambroxol free base.
The step c) of stirring the reaction mass after hydrochloride salt according to the present invention, followed by step b) performed for 2-5 hours particularly for 3h ours by maintaining the temperature ranges between 15-25°C particularly 18-22°C. The stirring of reaction mass after salt formation is required to gain uniformity in the reaction mass resulting the desired salt formation.
The step d) of filtering the reaction mass is performed under vacuum to isolate the highly pure crystalline Ambroxol Hydrochloride, which was observed to be having purity exceeding 99.8% (HPLC area%).
The optional step of purification as step e) for the purification of Ambroxol Hydrochloride may be performed by using acetone in a ratio of 1:1.5 at temperature ranging between 25-30°C, followed by stirring for about 1-2 hours.The reaction mass is filtered and washed the wet cake with acetone suitably. Drying of the wet cake was performed under vacuum for about 8-10 hrs at 65-70°C for achieving the desired drying characteristics of the Pharma grade API.
The Pharma grade API obtained as crystalline Ambroxol hydrochloride was found to be highly pure crystalline material (designated as Form-SAH) having purity exceeding 99.8% (by HPLC). This highly pure crystalline Ambroxol Hydrochloride (Form-SAH), is characterized by cis-4-[(2-amino-3,5-dibromobenzyl]amino] cyclohexanol and trans-[4-(6,8-dibromo-1,4-dihydroquinazoline-3 (H)] cyclohexanol hydrochloride content of less than 0.02% and (2-amino-3,5-dibromophenyl) formaldehyde content is absent.
In another embodiment of the present invention, it provides highly pure crystalline Ambroxol Hydrochloride designated as Form-SAH, characterized by X-ray powder diffraction pattern comprising of 2?° diffraction angle peaks at 7.1, 13.0, 15.8, 17.5, 20.6, 21.2, 22.6, 23.5, 24.0, 25.1, 27.6, 28.4, 32.2, 35.7 ± 0.2 2?°.
Crystalline Ambroxol Hydrochloride Form-SAH is further characterized by FT-IR spectral absorption peaks selected from 1778 cm-1, 1632 cm-1, 1300 cm-1, 1285 cm-1, 658 cm-1, 634 cm-1, 578 cm-1 and 541 cm-1 ; and DSC isotherm endothermic peak ranging between 243-246°C.
Crystalline Ambroxol Hydrochloride - Form-SAH has shown X-ray powder diffraction pattern, substantially according to FIG. 1 and exhibiting a doublet diffraction angle peak at 6.7 and 7.1 ± 0.2 2?°, IR absorption spectrum substantially according to FIG. 2 and DSC thermogram pattern substantially according to FIG. 3.
In yet another embodiment of the present invention, it provides a pharmaceutical composition comprising highly pure Crystalline Form-SAH of Ambroxol Hydrochloride and at least one or more pharmaceutically acceptable excipients.
The Crystalline Ambroxol Hydrochloride (I) Form-SAH as highly pure and stable material obtained by the process of the present application may be formulated as solid compositions for oral administration in the form of syrup, capsules, tablets, pills, powders, or granules useful as antitussive in the treatment of acute and chronic disease of the respiratory tract associated with abnormal bronchial secretions in particular acute attacks of chronic bronchitis, asthmatic bronchitis, bronchial asthma. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions.
Pharmaceutically acceptable excipients used in the compositions comprising Crystalline Ambroxol Hydrochloride (I) Form-SAH of the present application include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.
Pharmaceutically acceptable excipients used in the compositions derived from Crystalline Ambroxol Hydrochloride (I) Form-SAH of the present application may also comprise to include the pharmaceutically acceptable carrier(s) used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.
The term " pharmaceutical composition" or "oral pharmaceutical composition" comprises capsule, tablet (film coated tablet, controlled release tablet, modified release tablet, delayed release, immediate release etc.), micro tablet, powder, granule and pellets. Capsules used as oral dosage form can be soft or hard capsules, though oral dosage form of the present invention is tablet or capsule.
The term "about" is a value that can be considered ±5% of the given value. Based on context of discussion, the term "% w/w" refers to the relative value to total weight of granules or to total weight of pharmaceutical composition and “%v/v” refer to volume by total volume percentage.
Usage of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The term wt % refers to percent by weight. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g. "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.
The terms “pharmaceutically acceptable excipients”, “pharmaceutically compatible excipients”, and “excipients” are used interchangeably in this disclosure. They refer to non-API substances such as disintegrators, binders, fillers, and lubricants used in formulating pharmaceutical composition. They are generally safe for administering to humans according to established governmental standards, including those promulgated by the United States Food and Drug Administration.
Particular embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those particular embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in best possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
While the forgoing pages provide a detailed description of the preferred embodiments of the invention, it is being understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense
EXAMPLES
The process for preparation of crystalline form-SAH of Ambroxol Hydrochloride (I) according to the present invention is performed in the below mentioned manner:

Example-01: Process for preparation of crystalline Ambroxol Hydrochloride

Step (a):
125gm of Ambroxol free base was charged into a reaction flask containing 688ml of acetone at room temperature and stir until a clear solution is obtained. Charged 3.38 gm activated charcoal and stir for 20-30mins at room temperature. Filter the reaction mass through hyflo bed and washed the hyflo bed with 100ml of acetone. Collect the filtrate and charged it into a clean reaction flask. Cool the reaction mass upto 18-22°C and gradually add 32ml of concentrated hydrochloride acid within a time interval. After completion of Hydrochloric acid addition, the pH of the reaction mass is maintained in the range of 1.2-1.6. Stir the reaction mass for 3hrs at 18-22°C. Filter the reaction mass under vacuum and washed the wet cake with 40ml of acetone. Suck dry the wet cake under vacuum for 1-1.5hrs.
Step (b):
Charge the wet cake (135gm) into a reaction flask containing 200ml acetone and stir at 25-30°C for 1-1.5hr. Filter the reaction mass at 25-30°C and wash the wet cake with 10ml acetone. Dry the wet cake under vacuum for 9-10hrs at 65-70°C.
Dry Weight: 130gm
YIELD: 94.8%
HPLC Purity: 99.92%
LOD: 0.166%
Example-02: Process for preparation of crystalline Ambroxol Hydrochloride

Step (a):
125gm of Ambroxol free base was charged into a reaction flask containing 750ml of acetone at 25-30°C until a clear solution is obtained. Charged 3.38gm activated charcoal and stir at the same temperature for 20-30mins. Filter the reaction mass through hyflo bed and washed the hyflo bed with 100ml of acetone. Collect the filtrate and charge it into a clean reaction flask. Cool the reaction mass to 18-22°C and add 32ml of concentrated Hydrochloride acid within a time interval of 2-3hrs at a temperature range of 18-22°C. After completion of Hydrochloric acid addition, the pH of the reaction mass is maintained in the range of 1.2-1.6. Stir the reaction mass for 3hrs at 18-22°C. Filter the reaction mass under vacuum and washed the wet cake with 40ml of acetone. Suck dry the wet cake under vacuum for 1-2hrs.
Step (b):
Charge the wet cake (133gm) into a reaction flask containing 200ml acetone and stir at 25-30°C for 1hr. Filter the reaction mass at 25-30°C and wash the wet cake with 10ml acetone. Dry the wet cake under vacuum for 8-10hrs at 65-70°C .
Dry Weight: 130gm
YIELD: 94.8%
HPLC Purity: 99.82%
LOD: 0.23%
Example-03: Process for preparation of crystalline Ambroxol Hydrochloride (I)

Step (a):
100gm of Ambroxol free base was charged into a reaction flask containing 650ml of acetone at room temperature till a clear solution is obtained. Charged 2.70gm activated charcoal and stir at room temperature for 20-30mins. Filter the reaction mass through hyflo bed and washed the hyflo bed with 100ml of acetone. Collect the filtrate and charge it into a clean reaction flask. Cool the reaction mass to 18-22°C and gradually add 25ml of concentrated Hydrochloride acid within a time interval of 2-3hrs at 18-22°C. After completion of Hydrochloric acid addition, the pH of the reaction mass is maintained in the range of 1.2-1.6. Stir the reaction mass for 3hrs at 18-22°C. Filter the reaction mass and washed with 32ml of acetone.
Step (b):
Charge the wet cake (108gm) into a reaction flask containing 160ml acetone and stir at 25-30°C for 1hr. Filter the reaction mass at 25-30°C and wash the wet cake with 10ml acetone. Dry the wet cake under vacuum for 9-10hrs at 65-70°C.
Dry Weight: 105gm
YIELD: 95.8%
HPLC Purity: 99.9%
Example-04: Process for preparation of crystalline Ambroxol Hydrochloride (I)

Step (a):
100gm of Ambroxol free base was charged into a reaction flask containing 550ml of methylethylketone at 25-30°C until a clear solution is obtained. Charged 2.70gm activated charcoal and stir at 25-30°C for 20-30mins. Filter the reaction mass through hyflo bed and washed the hyflobed with 100ml of methylethylketone. Collect the filtrate and charged it into a clean reaction flask. Cool the reaction mass to 18-22°C and add 25ml of concentrated Hydrochloride acid within a time interval of 2-3hrs at 18-22°C. After completion of Hydrochloric acid addition, the pH of the reaction mass is maintained in the range of 1.2-1.6. Stir the reaction mass for 3hrs at 18-22°C. Filter the reaction mass and washed the wet cake with 32ml of methylethylketone.
Step (b):
Charge the wet cake (105gm) into a reaction flask containing 150ml methylethylketone and stir at 25-30°C for 1hr. Filter the reaction mass at 25-30°C and wash the wet cake with 10ml methylethyl ketone. Dry the wet cake under vacuum for 9-10hrs at 65-70°C.
Dry Weight: 102.5 gm
YIELD: 93.5%
HPLC Purity: 99.89%

Claims:We Claim,
1. A process for preparing crystalline Ambroxol Hydrochloride (I)
(I)
comprising the steps of:
f) treating Ambroxol free base with ketone (C3-C6) solvent in a ratio ranging between 1 (Ambroxol base) : 4 -7 (ketone solvent) (w/v);
g) adding concentrated hydrochloric acid till achieving pH range between 1.2 to 1.6 in time duration ranging between 2-5 hours at temperature ranging between 15-25°C
h) stir the reaction mass of step b) for time duration ranging between 2-5 hours at temperature ranging between 15-25°C
i) filter the crystalline Ambroxol Hydrochloride
j) Optionally purify the crystalline Ambroxol Hydrochloride with a ketone (C3-C6) solvent to get crystalline Ambroxol Hydrochloride.
2. A process for preparation of crystalline Ambroxol hydrochloride according to claim-1, wherein the ketone (C3-C6) solvent used in step (a) and step (e) is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone.
3. A process for preparation of crystalline Ambroxol hydrochloride according to claim-1, wherein the temperature in step (b) is maintained preferably in the range between 18-22°C.
4. A process for preparation of crystalline Ambroxol hydrochloride according to claim-1, wherein obtained crystalline Ambroxol hydrochloride in step d) or e) is a highly pure crystalline material (designated as Form-SAH) having purity exceeding 99.8% (by HPLC).
5. Crystalline Ambroxol Hydrochloride designated as Form-SAH, characterized by X-ray powder diffraction pattern comprising of 2?° diffraction angle peaks at 7.1, 13.0, 15.8, 17.5, 20.6, 21.2, 22.6, 23.5, 24.0, 25.1, 27.6, 28.4, 32.2, 35.7 ± 0.2 2?°.
6. Crystalline Ambroxol Hydrochloride Form-SAH according to claim 5, is further characterized by FT-IR spectral absorption peaks selected from 1778 cm-1, 1632 cm-1, 1300 cm-1, 1285 cm-1, 658 cm-1, 634 cm-1, 578 cm-1 and 541 cm-1 ; and DSC isotherm endothermic peak ranging between 243-246°C.
7. Highly pure crystalline Ambroxol Hydrochloride designated as Form-SAH, according to claim-4, wherein the Crystalline Form-SAH is characterized by cis-4-[(2-amino-3,5-dibromobenzyl]amino] cyclohexanol and trans-[4-(6,8-dibromo-1,4-dihydroquinazoline-3 (H)] cyclohexanol hydrochloride content less than 0.02% and (2-amino-3,5-dibromophenyl) formaldehyde content is absent.
8. Crystalline Ambroxol Hydrochloride designated as Form-SAH according to claim-5 is further characterized by X-ray powder diffraction pattern, substantially according to FIG. 1 and exhibiting a doublet diffraction angle peak at 6.7 and 7.1 ± 0.2 2?°, IR absorption spectrum substantially according to FIG. 2 and DSC thermogram pattern substantially according to FIG. 3.
9. A pharmaceutical composition comprising highly pure Crystalline Form-SAH of Ambroxol Hydrochloride and at least one or more pharmaceutically acceptable excipients.